Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation

Luika A. Timmerman, Joaquín Grego-Bessa, Angel Raya, Esther Bertrán, José María Pérez-Pomares, Juan Díez, Sergi Aranda, Sergio Palomo, Frank McCormick, Juan Carlos Izpisua Belmonte, José Luis De La Pompa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

692 Scopus citations

Abstract

Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types. In the embryonic heart, Notch functions via lateral induction to promote a selective transforming growth factor-β (TGFβ)-mediated EMT that leads to cellularization of developing cardiac valvular primordia. Embryos that lack Notch signaling elements exhibit severely attenuated cardiac snail expression, abnormal maintenance of intercellular endocardial adhesion complexes, and abortive endocardial EMT in vivo and in vitro. Accordingly, transient ectopic expression of activated Notchl (N1IC) in zebrafish embryos leads to hypercellular cardiac valves, whereas Notch inhibition prevents valve development. Overexpression of N1IC in immortalized endothelial cells in vitro induces EMT accompanied by oncogenic transformation, with corresponding induction of snail and repression of VE-cadherin expression. Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis.

Original languageEnglish (US)
Pages (from-to)99-115
Number of pages17
JournalGenes and Development
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2004

Keywords

  • EMT
  • Endocardium
  • Lateral induction
  • Notch
  • Snail
  • TGFβ

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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